Limited Metastatic Potential Research Articles

Comparative transcriptomic analyses reveal activation of the epithelial-mesenchymal transition program in non-metastasizing low grade pseudomyxoma peritonei

Epithelial-mesenchymal transition (EMT), angiogenesis, cell adhesion and extracellular matrix (ECM) interaction are essential for colorectal cancer (CRC) metastasis. Low grade mucinous neoplasia of the appendix (LAMN) and its advanced state low grade pseudomyxoma peritonei (lgPMP) show local aggressiveness with very limited metastatic potential as opposed to CRC. To better understand the underlying processes that foster or impede metastatic spread, we compared LAMN, lgPMP, and CRC with respect to their molecular profile with subsequent pathway analysis.LAMN, lgPMP and (mucinous) CRC cases were subjected to transcriptomic analysis utilizing Poly(A) RNA sequencing. Successfully sequenced cases (LAMN n = 10, 77%, lgPMP n = 13, 100% and CRC n = 8, 100%) were investigated using bioinformatic and statistical tests (differential expression analysis, hierarchical clustering, principal component analysis and gene set enrichment analysis).We identified a gene signature of 28 genes distinguishing LAMN, lgPMP and CRC neoplasias. Ontology analyses revealed that multiple pathways including EMT, ECM interaction and angiogenesis are differentially regulated. Fifty-three significantly differentially regulated gene sets were identified between lgPMP and CRC followed by CRC vs. LAMN (n = 21) and lgPMP vs. LAMN (n = 16). Unexpectedly, a substantial enrichment of the EMT gene set was observed in lgPMP vs. LAMN (FDR=0.011) and CRC (FDR=0.004). Typical EMT markers were significantly upregulated (Vimentin, TWIST1, N-Cadherin) or downregulated (E-Cadherin) in lgPMP. However, MMP1 and MMP3 levels, associated with EMT, ECM and metastasis, were considerably higher in CRC.We show that the different tumor biological behaviour and metastatic spread pattern of midgut malignancies is reflected in a different gene expression profile. We revealed a strong activation of the EMT program in non-metastasizing lgPMP vs. CRC. Hence, although EMT is considered a key step in hematogenous spread, successful EMT does not necessarily lead to hematogenous dissemination. This emphasizes the need for further pathway analyses and forms the basis for mechanistic and therapy-targeting research.

Mathematical prediction with pretreatment growth rate of metastatic cancer on outcomes: implications for the characterization of oligometastatic disease.

Oligometastatic disease (OMD) represents an indolent cancer status characterized by slow tumor growth and limited metastatic potential. The use of local therapy in the management of the condition continues to rise. This study aimed to investigate the advantage of pretreatment tumor growth rate in addition to baseline disease burden in characterizing OMDs, generally defined by the presence of ≤ 5 metastatic lesions. The study included patients with metastatic melanoma treated with pembrolizumab. Gross tumor volume of all metastases was contoured on imaging before (TP-1) and at the initiation of pembrolizumab (TP0). Pretreatment tumor growth rate was calculated by an exponential ordinary differential equation model using the sum of tumor volumes at TP-1 and TP0 and the time interval between TP-1. and TP0. Patients were divided into interquartile groups based on pretreatment growth rate. Overall survival, progression-free survival, and subsequent progression-free survival were the study outcomes. At baseline, median cumulative volume and number of metastases were 28.4 cc (range, 0.4-1194.8 cc) and 7 (range, 1-73), respectively. The median interval between TP-1 and TP0 was -90 days and pretreatment tumor growth rate (×10-2 days-1) was median 4.71 (range -0.62 to 44.1). The slow-paced group (pretreatment tumor growth rate ≤ 7.6 ×10-2 days-1, the upper quartile) had a significantly higher overall survival rate, progression-free survival, and subsequent progression-free survival compared to those of the fast-paced group (pretreatment tumor growth rate > 7.6 ×10-2 days-1). Notably, these differences were prominent in the subgroup with >5 metastases. Pretreatment tumor growth rate is a novel prognostic metric associated with overall survival, progression-free survival, and subsequent progression-free survival among metastatic melanoma patients, especially patients with >5 metastases. Future prospective studies should validate the advantage of disease growth rate plus disease burden in better defining OMDs.

Abstract 962: A hybrid epithelial-mesenchymal phenotype identifies lung cancer cells with high metastatic potential due to increased stemness properties and escape from NK immunosurveillance

Abstract Introduction: Epithelial to mesenchymal transition (EMT) is essential for cancer dissemination but its role in overt metastasis establishment remains an open issue. Multiple EMT states and great phenotypic plasticity have also been described, indicating the need for in-depth characterization of biological properties associated with different EMT phenotypes. The so-called hybrid phenotype, characterized by presence of both mesenchymal and epithelial markers, might in fact identify cancer cells with enhanced metastatic propensity. Materials and Methods: To assess the metastatic potential of different EMT phenotypes, we exploited two lung cancer cell lines with different properties (A549/epithelial and LT73/hybrid) and generated their respective sublines through four sequential rounds of in vitro migration assay (named M4). TGFβ treatment was also used to induce EMT. With a previously validated score based on the ratio between expression of epithelial (CDH1) or mesenchymal genes (SNAI2), cells were classified as: epithelial (A549)>hybrid (A549-M4, LT73)>mesenchymal (LT73-M4, A549-TGFβ). The disseminating/metastatic properties of the different lines were tested in vivo by subcutaneous and tail-vein injections in SCID mice. Interaction with NK cells (NKs), known to specifically target EMT cancer cells, was also assessed. Results and Discussion: Compared to parental cells, M4 cells showed up-regulation of EMT-associated genes, expansion of the subset of CD133+ lung cancer stem cells (CSC) and displayed in vivo higher ability to disseminate from primary tumors to murine lungs (2-fold change, p=0.004). However, hybrid cells (LT73 and A549-M4) showed an increased ability to generate overt lung metastases in experimental metastasis assays compared to either epithelial (A549) or mesenchymal cells (LT73-M4 and A549-TGFβ). The higher metastatic ability of hybrid cells was correlated with CSCs expansion and reduced NKs infiltration to the metastatic lungs. Expression of IL-8, a cytokine involved in NKs recruitment, was decreased in hybrid cells and they were less prone to chemoattract NKs in vitro compared to both epithelial and mesenchymal cells. Finally, in vivo prevention of NKs recruitment to the lungs using a neutralizing antibody, massively increased metastasis formation and expansion of CSCs in mice injected i.v. with mesenchymal A549-TGFβ (p=0.0006), but had limited effects in groups injected with both epithelial A549 and hybrid A549-M4. Conclusions: Our data indicate that the hybrid phenotype correlates with the highest metastatic potential related to efficient cancer cell dissemination, increased induction of stemness features and ability to avoid NKs recruitment. Conversely, fully mesenchymal cells show limited metastatic potential, possibly due the control exerted by NKs on their CSC subsets. Citation Format: Giulia Bertolini, Monica Parodi, Massimo Milione, Fabio Murianni, Giovanni Centonze, Giulia Taiè, Gabriella Sozzi, Massimo Vitale, Luca Roz. A hybrid epithelial-mesenchymal phenotype identifies lung cancer cells with high metastatic potential due to increased stemness properties and escape from NK immunosurveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 962.

TGFβ selects for pro-stemness over pro-invasive phenotypes during cancer cell epithelial-mesenchymal transition.

Transforming growth factor β (TGFβ) induces epithelial–mesenchymal transition (EMT), which correlates with stemness and invasiveness. Mesenchymal–epithelial transition (MET) is induced by TGFβ withdrawal and correlates with metastatic colonization. Whether TGFβ promotes stemness and invasiveness simultaneously via EMT remains unclear. We established a breast cancer cell model expressing red fluorescent protein (RFP) under the E‐cadherin promoter. In 2D cultures, TGFβ induced EMT, generating RFPlow cells with a mesenchymal transcriptome, and regained RFP, with an epithelial transcriptome, after MET induced by TGFβ withdrawal. RFPlow cells generated robust mammospheres, with epithelio‐mesenchymal cell surface features. Mammospheres that were forced to adhere generated migratory cells, devoid of RFP, a phenotype which was inhibited by a TGFβ receptor kinase inhibitor. Further stimulation of RFPlow mammospheres with TGFβ suppressed the generation of motile cells, but enhanced mammosphere growth. Accordingly, mammary fat‐pad‐transplanted mammospheres, in the absence of exogenous TGFβ treatment, established lung metastases with evident MET (RFPhigh cells). In contrast, TGFβ‐treated mammospheres revealed high tumour‐initiating capacity, but limited metastatic potential. Thus, the biological context of partial EMT and MET allows TGFβ to differentiate between pro‐stemness and pro‐invasive phenotypes.

Abstract ES9-3: Oligo-progressive disease. Treating locally more than systemically

Abstract Advances in cancer therapies and technologies have shifted the paradigm for treating metastatic disease. Patients with stage IV disease are living longer and technologic advances enable us to deliver local therapies, such as surgical resection, radiofrequency ablation, or stereotactic radiosurgery, with lower toxicities. Genetic deep sequencing has helped us understand metastases to be genetically heterogeneous with independent subpopulations evolving in response to environmental pressures. We currently understand metastatic progression from primary tumor to disseminated disease to involve multiple stages, raising the possibility of an intermediate, curable, oligometastatic state with limited metastatic potential. The clinical relevance of oligometastases has been validated in multiple, recent randomized clinical trials. Metastasis directed therapies have been demonstrated to improve overall survival, however, this benefit is not seen in all patients, and breast specific data are lacking. This educational presentation will review randomized evidence supporting local treatment of oligometastases. We will also review evidence specific to breast cancer and highlight the critical need to define when local therapies can be effective at disrupting metastatic progression in breast cancer patients. Citation Format: A Xu. Oligo-progressive disease. Treating locally more than systemically [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES9-3.

Glycosyltransferase ST6Gal-I promotes the epithelial to mesenchymal transition in pancreatic cancer cells

ST6Gal-I, an enzyme upregulated in numerous malignancies, adds α2-6-linked sialic acids to select membrane receptors, thereby modulating receptor signaling and cell phenotype. In this study, we investigated ST6Gal-I’s role in epithelial to mesenchymal transition (EMT) using the Suit2 pancreatic cancer cell line, which has low endogenous ST6Gal-I and limited metastatic potential, along with two metastatic Suit2-derived subclones, S2-013 and S2-LM7AA, which have upregulated ST6Gal-I. RNA-Seq results suggested that the metastatic subclones had greater activation of EMT-related gene networks than parental Suit2 cells, and forced overexpression of ST6Gal-I in the Suit2 line was sufficient to activate EMT pathways. Accordingly, we evaluated expression of EMT markers and cell invasiveness (a key phenotypic feature of EMT) in Suit2 cells with or without ST6Gal-I overexpression, as well as S2-013 and S2-LM7AA cells with or without ST6Gal-I knockdown. Cells with high ST6Gal-I expression displayed enrichment in mesenchymal markers (N-cadherin, slug, snail, fibronectin) and cell invasiveness, relative to ST6Gal-I-low cells. Contrarily, epithelial markers (E-cadherin, occludin) were suppressed in ST6Gal-I-high cells. To gain mechanistic insight into ST6Gal-I’s role in EMT, we examined the activity of epidermal growth factor receptor (EGFR), a known EMT driver. ST6Gal-I-high cells had greater α2-6 sialylation and activation of EGFR than ST6Gal-I-low cells. The EGFR inhibitor, erlotinib, neutralized ST6Gal-I-dependent differences in EGFR activation, mesenchymal marker expression, and invasiveness in Suit2 and S2-LM7AA, but not S2-013, lines. Collectively, these results advance our understanding of ST6Gal-I’s tumor-promoting function by highlighting a role for ST6Gal-I in EMT, which may be mediated, at least in part, by α2-6-sialylated EGFR.

Definition, Biology, and History of Oligometastatic and Oligoprogressive Disease.

Historical theories of metastasis have been informed by the seed and soil hypothesis, the Halsteadian paradigm proposing an orderly spread from local to distant sites, and the presumption that cancer is an inherently systemic process even in the earliest cases. The more contemporary spectrum theory now suggests that the propensity for distant spread exists along a continuum of metastatic virulence. Tumors with limited metastatic potential represent one subset along this spectrum that could potentially be cured with local ablative therapy. Integrating clinical and molecular features to biologically inform the classification of not only oligometastatic or oligoprogressive disease but also the entire metastatic spectrum holds great promise to improve prognostication and inform clinical decision making. To this end, the inclusion of molecular correlative studies and biospecimen collection on prospective protocols is imperative.

GR01.01 Definition and Minimal Staging in Oligometastatic Disease

Oligometastatic non-small cell lung cancer (NSCLC) is perceived as a separate entity of metastatic NSCLC with limited metastatic potential and possibility of long term survival when treated with local radical treatment1-3. However, uniform definition of oligometastatic NSCLC does not exist. We showed in a recent systematic review (21 papers) that the number of metastasis, allowed in the definition of oligometastatic NSCLC, varies between 1 and 8, in only 2 out of 21 papers > 5 metastasis were allowed4. This has led to an European Organisation on Research and Treatment of Cancer (EORTC) –Lung Cancer Group (LCG) initiative to formulate a consensus definition of synchronous oligometastatic NSCLC. A pan-European multidisciplinary consensus group was established. Results from the systematic review, a European survey and real patient cases were taken into account when. It was concluded that the definition of synchronous oligometastatic NSCLC is relevant when a radical treatment is technically feasible for all tumor sites with acceptable toxicity, that may modify the disease course leading to long-term disease control. Based on the review, a maximum of 5 metastases and 3 organs is proposed. Mediastinal lymph node involvement is not counted as a metastatic site5. In addition staging with PET-CT and imaging of the brain is mandatory. This is in line with the advice of the EORTC-imaging group6. The eligibility criteria of recent and ongoing clinical trials in this setting will be discussed in this presentation. 1. Gomez D, Tang C, Zhang J, et al. Local Consolidative Therapy (LCT) Improves Overall Survival (OS) Compared to Maintenance Therapy/Observation in Oligometastatic Non-Small Cell Lung Cancer (NSCLC): Final Results of a Multicenter, Randomized, Controlled Phase 2 Trial. ASTRO 2018 2018;abstract LBA3. 2. Gomez DR, Blumenschein GR, Jr., Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. The lancet oncology 2016;17:1672-1682. 3. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA oncology 2018;4:e173501. 4. GiajLevra N, Levra MG, Durieux V, et al. Defining synchronous oligometastatic non-small cell lung cancer: a systematic review. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2019. 5. Dingemans A, Hendriks L, Berghmans T, et al. MA25.02 - Searching for a Definition of Synchronous Oligometastatic (sOMD)-NSCLC: A Consensus from Thoracic Oncology Experts WCLC 2018. Toronto: 2018:abstract MA 25.02. 6. deSouza NM, Liu Y, Chiti A, et al. Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group. European journal of cancer 2018;91:153-163. Non-Small Cell Lung Cancer, Oligometastatic

3047 A Tale of Two Tumors: Peritoneal Malignancies

INTRODUCTION: Pseudomyxoma peritonei (PMP) and malignant peritoneal mesothelioma (MPM) are rare malignancies of the peritoneum that present in similar fashion. We describe one case of each to illustrate the diagnostic and therapeutic challenges associated with these tumors. CASE DESCRIPTION/METHODS: Case 1: A 67 year old Ukrainian male presented with a chief compliant of 6 months abdominal pain and fever. Physical exam revealed abdominal distension. A CT scan showed infiltrative densities of the omentum and mesenteric fat suggesting an inflammatory process. CRP and ESR were elevated. Colonoscopy was unremarkable. His abdominal pain continued to worsen. A repeat CT showed progressive omental densities (Figure 2a). An initial percutaneous omental biopsy showed atypical mesothelia cells. Subsequent exploratory laparotomy with targeted biopsies revealed a diagnosis of MPM (Figure 3a). He was initiated on hyperthermic intraperitoneal chemotherapy (HIPEC) with possible future cytoreductive surgery (CRS). Case 2: A 75 year old Nepali male presented with a chief complaint of abdominal pain, distension and weight loss. An outpatient ultrasound several months prior had demonstrated septated ascites. Physical exam revealed a markedly distended abdomen. A CT scan showed diffuse peritoneal and omental thickening (Figure 2b). An Omental biopsy was performed and pathology revealed pseudomyxoma peritonei (PMP) (Figure 3b). A colonoscopy revealed mucinous material at the appendiceal orifice (Figure 1). Following laparoscopy, he was not deemed a candidate for CRS with HIPEC due to burden of disease. DISCUSSION: PMP and MPM are rare tumors of the peritoneum that typically present with non-specific signs and symptoms.1,2 As a result, diagnosis is often delayed and occurs late in the progression of disease. Both PMP and MPM defy typical TNM staging as spread is predominately expansive rather than infiltrative. This pattern of spread gives limited extra-abdominal metastatic potential. As a consequence, these tumors tend to remain confined to the abdominal cavity. First line therapy for both PMP and MPM is CRS and HIPEC.3,4 Candidacy is determined by the peritoneal cancer index (PCI), a scoring system based on extent of peritoneal tumor burden visualized on laparoscopy.5 Systemic chemotherapy is an option for patients ineligible for CRS and HIPEC. Ideal chemotherapy regimens remain unclear as no randomized controlled trials exist.1,2 Intraperitoneal mucolytics remain under investigation as a potential therapy unique to PMP.6

Verrucous carcinoma arising in a long standing Buschke-Löwenstein tumor.

Key Clinical MessageGiant condyloma acuminatum is a rare variant of genital warts also known as Buschke‐Löwenstein tumor. It is characterized by a slow progression of exophytic, ulcerative, and cauliflower‐shaped tumor with benign histological features. Verrucous carcinoma however is a rare variant of well‐differentiated squamous cell carcinoma with limited metastatic potential.

Editorial Comment

Over the last 20 years, our understanding of renal cortical tumors (RCT) and their best management has evolved. Formerly, surgeons felt that tumors of all sizes and locations were best managed by radical nephrectomy (RN) if there was a functional contra lateral kidney. Partial nephrectomy (PN), initially used sparingly, was reserved for essential indications such as tumor in a solitary kidney, tumor in a patient with renal calculus disease or renal insufficiency, and for patients with bilateral renal tumors. Now we understand that RCT are a complex family of tumors with at least 31 separate subtypes described based on genomic and metabolomic studies. 1 Chen F. Zhang Y. Şenbabaoğlu Y. et al. Multilevel genomics-based taxonomy of renal cell carcinoma. Cell Rep. 2016; 14 (Epub 2016 Mar 3): 2476-2489https://doi.org/10.1016/j.celrep.2016.02.024 Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar , 2 Hakimi A.A. Reznik E. Lee C.H. et al. An integrated metabolic atlas of clear cell renal cell carcinoma. Cancer Cell. 2016; 29: 104-116https://doi.org/10.1016/j.ccell.2015.12.004 Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar These tumors pose a spectrum of oncologic threats ranging from benign (20%), indolent with limited metastatic potential (25%), and malignant (55%). This variable threat from RCT coupled with the understanding that PN provides equivalent tumor control to RN while at the same time preserving renal function, preventing, or delaying chronic kidney disease and its associated cardiovascular disease lead to enhanced utilization of PN in the elective setting. 3 Russo P. Oncological and renal medical importance of kidney-sparing surgery. Nat Rev Urol. 2013; 10: 292-299 Crossref PubMed Scopus (25) Google Scholar

Oligometastatic prostate cancer: Reality or figment of imagination?

The term “oligometastatic prostate cancer” refers to a heterogeneous group of disease states currently defined solely on the basis of clinical features. Oligorecurrent disease, de novo oligometastases, and oligoprogressive disease likely have unique biologic underpinnings and natural histories. Evidence suggesting the existence of a subset of patients who harbor prostate cancer with limited metastatic potential currently includes disparate and overwhelmingly retrospective reports. Nevertheless, emerging prospective data have corroborated the “better‐than‐expected,” retrospectively observed outcomes, particularly in the setting of oligorecurrent prostate cancer. Improved functional imaging with prostate‐specific membrane antigen‐targeted strategies may enhance the identification of patients with oligometastatic prostate cancer in the short term. In the long term, refinement of the oligometastatic case definition likely will require biologic risk‐stratification schemes. To determine optimal treatment strategies and identify patients most likely to benefit from metastasis‐directed therapy, future efforts should focus on conducting high‐quality, prospective trials with much‐needed molecular correlative studies.

Erratum to inequivalence of non-aggressiveness in clinically diagnosed lung cancers and overdiagnosis in lung cancer screening trials.

[This corrects the article DOI: 10.21037/jtd.2018.01.164.].

The biology of prostate cancer metastases: does oligo differ from polymetastatic?

To examine the studies of prostate cancer biology, which evaluated oligometastatic and polymetastatic disease to identify data supporting differences between them. Studies of tumor biology suggest that malignant cells of limited metastatic potential exist, which may explain the phenomenon of oligometastatic disease. Conversely, oligometastatic disease may represent earlier presentation of polymetastatic disease in a proportion of cases. Data suggest molecular differences between oligo and polymetastatic disease, although larger studies are required to validate these results. Micro RNA differences between oligo and polymetastatic disease appear especially intriguing, which may regulate gene expression and modulate metastatic potential. Although metastatic prostate cancer is traditionally treated by systemic therapy alone, the concept of oligometastatic disease prompting ablative therapy of metastases is emerging. Better understanding of the molecular alterations driving oligometastatic disease may help tailor therapy for these patients, by helping discriminate between true oligometastatic disease and disease destined to progress to polymetastatic status.

Extrapleural solitary fibrous tumour with malignant histological features: a case report and review of current and emerging prognostic factors

Solitary fibrous tumour (SFT) is a mesenchymal neoplasm, historically considered to be a tumour of the pleura with limited metastatic potential. Over time, evidence has shown that SFTs are anatomically ubiquitous, possess a NAB2-STAT6 gene fusion, and can behave aggressively, resulting in local recurrence, metastasis and death. Attempts have subsequently been made to identify factors that can be used to predict which tumours will behave aggressively. We report a case of a 57 year old woman presenting with a longstanding pelvic mass, which was resected and a diagnosis of malignant solitary fibrous tumour was made, based on the features of increased mitotic activity and tumour necrosis, as per the 2013 WHO classification of tumours of soft tissue and bone. A review of recent literature shows increased mitotic rate is the feature most consistently reported to correlate with a poor outcome. Other features such as older patient age, larger tumour size, site of primary tumour and tumour necrosis are reported by some authors to correlate with aggressive behaviour. There may be a future role for molecular based prognostic indicators, with an initial investigation into the molecular alterations in SFT suggesting there are specific genotypes of NAB2-STAT6 gene fusion that are associated with a malignant phenotype.

Esophageal Stricture Prevention after Endoscopic Submucosal Dissection.

Advances in diagnostic modalities and improvement in surveillance programs for Barrett esophagus has resulted in an increase in the incidence of superficial esophageal cancers (SECs). SEC, due to their limited metastatic potential, are amenable to non-invasive treatment modalities. Endoscopic ultrasound, endoscopic mucosal resection, and endoscopic submucosal dissection (ESD) are some of the new modalities that gastroenterologists have used over the last decade to diagnose and treat SEC. However, esophageal stricture (ES) is a very common complication and a major cause of morbidity post-ESD. In the past few years, there has been a tremendous effort to reduce the incidence of ES among patients undergoing ESD. Steroids have shown the most consistent results over time with minimal complications although the preferred mode of delivery is debatable, with both systemic and local therapy having pros and cons for specific subgroups of patients. Newer modalities such as esophageal stents, autologous cell sheet transplantation, polyglycolic acid, and tranilast have shown promising results but the depth of experience with these methods is still limited. We have summarized case reports, prospective single center studies, and randomized controlled trials describing the various methods intended to reduce the incidence of ES after ESD. Indications, techniques, outcomes, limitations, and reported complications are discussed.

Breast lesions of uncertain malignant nature and limited metastatic potential: proposals to improve their recognition and clinical management.

Breast lesions comprise a family of heterogeneous entities with variable patterns of presentation, morphology and clinical behaviour. The majority of breast lesions are classified traditionally into benign and malignant conditions and their behaviour can, in the vast majority of cases, be predicted with a reasonable degree of accuracy. However, there remain lesions which show borderline features and lie in a grey zone between benign and malignant, as their behaviour cannot be predicted reliably. Defined pathological categorization of such lesions is challenging, and for some entities is recognized to be subjective and include a range of diagnoses, and forms of terminology, which may trigger over- or undertreatment. The rarity of these lesions makes the acquisition of clinical evidence problematic and limits the development of a sufficient evidence base to support informed decision-making by clinicians and patients. Emerging molecular evidence is providing a greater understanding of the biology of these lesions, but this may or may not be reflected in their clinical behaviour. Herein we discuss some breast lesions that are associated with uncertainty regarding classification and behaviour, and hence management. These include biologically invasive malignant lesions associated with uncertain metastatic potential, such as low-grade adenosquamous carcinoma, low-grade fibromatosis-like spindle cell carcinoma and encapsulated papillary carcinoma. Other lesions of uncertain malignant nature remain, such as mammary cylindroma, atypical microglandular adenosis, mammary pleomorphic adenoma and infiltrating epitheliosis. The concept of categories of (1) breast lesions of uncertain malignant nature and (2) breast lesions of limited metastatic potential are proposed with details of which histological entities could be included in each category, and their management implications are discussed.

Vaikų dermatofibrosarkoma: klinikinis atvejis ir literatūros apžvalga

Dermatofibrosarcoma protuberans yra itin retas vaikų piktybinis navikas. Nurodoma, kad klasikinė dermatofibrosarkomos forma labai retai metastazuoja, o fibrosarkominei jos transformacijai dažnai būdingos metastazės. Mes aprašome išopėjusios dešiniosios šlaunies dermatofibrosarkomos atvejį septyniolikos metų berniukui. Navikas buvo radikaliai pašalintas. Po vienerių metų atkryčio nerasta.

Vaikų dermatofibrosarkoma: klinikinis atvejis ir literatūros apžvalga

Dermatofibrosarcoma protuberans is a very rare malignant neoplasm in children. It is reported that the classic form of dermatofibrosarcoma has a very limited metastatic potential, while a fibrosarcomous transformation of dermatofibrosarcoma protuberans has a much higher potential. We present a case of a 17-year-old boy with a huge ulcerated mass (17 x 15 cm) on his right thigh. At operation, the pathological diagnosis was dermatofibrosarcoma protuberans with a fibrosarcomous component. All lesions were removed by surgical excision with a margin of 1.5 to 3 cm. After one year, there is no evidence of tumor recurrence.

Lymphoepithelioma-like carcinoma of the skin in a Polish patient

Lymphoepithelioma-like carcinoma of the skin (LELCS) is a very rare cutaneous neoplasm with limited metastatic potential. It presents distinctive histopathologic features similar to undifferentiated nasopharyngeal carcinoma and clinical similarities with other skin neoplasms. We present the first case of LELCS in Polish patients. A 72-year-old woman presented with a 12 months’ history of painless, solitary tumor on the nose. A wide local excision was performed. There was no evidence of local recurrence 24 months after surgical treatment.